The present invention relates to bicyclic carbamates and related compounds, pharmaceutical compositions comprising such compounds, and the use of such compounds as antagonists of leukotriene D4. The compounds of this invention are useful in the treatment of asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases. This invention also relates to pharmaceutical compositions containing these compounds and to methods of blocking the leukotriene D4 receptor.
It is known that arachidonic acid (AA) is metabolized in mammals by two distinct pathways. The metabolism of arachidonic acid by cyclooxygenase enzymes results in the production of prostaglandins and thromboxanes. The other pathway of AA metabolism involves lipoxygenase enzymes and results in the production of a number of oxidative products called leukotrienes. The latter are designated by the LT nomenclature system, and one of the most significant products of the lipoxygenase metabolic pathway is the leukotriene D.sub.4. Leukotrienes participate in inflammatory reactions, exhibit chemotactic activities, stimulate lysosomal enzyme release and act as important factors in the immediate hypersensitivity reaction. For example, LTD4 is a potent bronchoconstrictor of the human bronchi.
The biological activity of the leukotrienes indicates that a rational approach to drug therapy to prevent, remove or ameliorate the symptoms of asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock and other inflammatory diseases must focus on either blocking the release of mediators of these conditions or antagonizing their effects. Thus, compounds which inhibit the biological effects of the leukotrienes are considered to be of value in treating such conditions defined above.